Using LanM Enzymes to Modify Glucagon-Like Peptides 1 and 2 in E.coli.

Selective modification of peptides is often exploited to improve pharmaceutically relevant properties of bioactive peptides like stability, circulation time, and potency. In Nature, natural products belonging to the class of ribosomally synthesized and post-translationally modified peptides (RiPPs) are known to install a number of highly attractive modifications with high selectivity. These modifications are installed by enzymes guided to the peptide by corresponding leader peptides that are removed as the last step of biosynthesis. Here, we exploit leader peptides and their matching enzymes to investigate the installation of D-Ala post-translationally in a critical position in the hormones, glucagon-like peptides (GLP) 1 and 2. We also offer insight into how precursor peptide design can modulate the modification pattern achieved.

Consensus recommendations on the role of nurses in headache care: A European e-Delphi study.

BACKGROUND: Nurses work at headache centres throughout Europe, and their care for migraine patients is acknowledged. However, the specific roles and tasks of nursing vary, and a unified understanding is lacking, posing challenges to knowledge sharing and research. OBJECTIVES: Using an e-Delphi study method, the objective is to obtain healthcare professional headache experts' opinions on nursing-specific roles and tasks and combine this into consensus statements for nurse recommendations for migraine treatment. METHODS: A three-round questionnaire study was conducted with nurses and neurologists from 18 specialised headache centres in 10 countries. In round 1, statements were compiled from a systematic examination of existing literature and expert opinions. In rounds 2 and 3, the experts rated the importance of statements (from round 1) on a 5-point Likert scale. Statements were analysed using a content analysis method, and the consensus of pre-defined statements was evaluated with gradually increased predetermined criteria using descriptive statistics. RESULTS: Twenty-one experts, representing all 10 countries, participated. The predetermined consensus of ≥70% agreement was reached for 42 out of the initial 63 statements. These statements formed the final recommendations within two themes: "The nurses' roles and tasks in the clinical setting" and "The nurses' roles and tasks in educating patients and colleagues." The consensus level of statements was strong, with 40% receiving unanimous agreement (100%) and 97% achieving relatively high agreement (>80%). CONCLUSION: Nursing plays a vital role with diverse tasks in migraine care. This study offers practical recommendations and a framework for nurses, equipping them with a clinical tool to enhance care and promote a coordinated approach to migraine treatment.

Neutron instrument concepts for a high intensity moderator at the European spallation source.

In the course of the Horizon 2020 project HighNESS, a second moderator concept has been developed for the European Spallation Source, which complements the currently built moderator and is optimized for high intensity with a large viewable surface area. In this work we introduce conceptual designs for neutron instruments for condensed matter research designed to make optimal use of the capabilities of this moderator. The focus is on two concepts for small-angle neutron scattering and one neutron imaging instrument, which are intended to complement corresponding instruments that are already under construction at the European Spallation Source. One small-angle neutron scattering instrument concept resembles a conventional pinhole collimator geometry and aims to profit from the proposed second moderator by enabling to illuminate larger samples and providing particularly high resolution, drawing on a 30 m collimation and corresponding detector distance. A second small-angle neutron scattering instrument concept adopts nested mirror optics that enable to efficiently exploit the large moderator size and provide high resolution by focusing on the detector. The neutron imaging instrument concept is a typical pinhole instrument that can be found at continuous sources and draws on the corresponding strengths of high flux and large homogeneous fields-of-view, while still providing moderate wavelength resolution for advanced imaging methods.

Kinesiophobia following anterior cruciate ligament reconstruction.

Kinesiophobia is an irrational and debilitating fear of physical movement frequently occurring following anterior cruciate ligament (ACL) reconstruction. It is a major limiting factor in return to sport after ACL reconstruction and is associated with worse knee function and increased risk of a secondary ACL rupture. Kinesiophobia can be identified using the Tampa Scale of Kinesiophobia. Addressing kinesiophobia early in rehabilitation is crucial, as it can lead to non-adherence to rehabilitation. While cognitive therapy has shown promise in treating kinesiophobia, further research is needed in this area.

Potential Risks and Benefits of Desiccated Thyroid Extract for the Treatment of Hypothyroidism: A Systematic Review.

Background: Desiccated thyroid extract (DTE) is no longer recommended for the treatment of hypothyroidism but is still in use. This review aimed to summarize the available literature on treatment with DTE in adult patients with hypothyroidism. Methods: The search was conducted up until January 6, 2024, in six electronic databases. Two reviewers independently screened all the search results. The retrieved studies compared DTE treatment with levothyroxine or combination therapy with liothyronine and levothyroxine. The primary outcome was quality of life (QoL), and the secondary outcomes included symptoms, treatment preference, adverse effects, thyroid hormone levels, thyroid autoantibodies, cardiovascular measures, and gene polymorphisms in deiodinase enzymes. Results: In the qualitative synthesis, we included nine nonrandomized studies of interventions (NRSIs), two randomized clinical trials (RCTs), and three case reports. The overall quality of evidence was moderate to very low for the various outcomes. The RCTs found no difference between treatments regarding QoL and symptom score assessments. In the NRSIs, symptom and QoL assessments were in favor of DTE. The included studies indicated that DTE may cause an increase in heart rate, lower body weight, and lower high-density lipoprotein compared with other treatment regimens, but results were conflicting. Conclusions: Most studies of DTE treatment are hampered by an inferior design, and data on long-term effects and side effects are lacking. Two RCTs could not demonstrate any difference in QoL or symptom scores when comparing DTE with other thyroid hormone substitutions. Future trials of DTE in patients with hypothyroidism should be based on adequate study designs, validated measures of QoL, patients with reduced QoL, and the assessment of biomarkers reflecting long-term adverse effects.

Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

PURPOSE: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). METHODS: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 µg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. RESULTS: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. CONCLUSION: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 µg selenium or placebo for 12 months improved QoL to the same extent.

Development of Quality of Life in Adolescents and Young Adults With Cancer Using a Patient Support Smartphone App: Prepost Interventional Study.

BACKGROUND: Adolescents and young adults often experience existential concerns in addition to side effects during a cancer trajectory, which they often carry alone. Thus, cohesion with other adolescents and young adults with cancer is essential but difficult due to the relatively small, widely dispersed nationwide population. In cocreation, a smartphone app has been developed and includes an information bank, a symptom tracker, and a social community platform, aiming to improve the quality of life (QoL) in this patient group. OBJECTIVE: This nationwide, multicenter study aimed to investigate the QoL in adolescents and young adults undergoing a cancer trajectory as they used the app for 6 weeks. METHODS: Via youth support initiatives, participants were recruited from hospitals in all regions of Denmark. Inclusion criteria were patients with cancer aged 15-29 years who either initiated any cancer treatment or started follow-up after cancer treatment within 30 days. Participants used the adolescents and young adults cancer app for 6 weeks. Before and after the 6 weeks of app use, they completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The participants were divided into a treatment and a follow-up group for analysis. A high score for a functional scale or the global health or overall QoL represents a high or healthy level of functioning or high QoL, respectively; however, a high score for a symptom scale or item represents a high level of symptomatology. RESULTS: Overall, 81 participants were recruited. However, 4 participants did not answer the questionnaire and 6 participants did not use the app. In the treatment group (n=36), significant improvement was found in 2 domains: "Role functioning" (baseline median 33.33, IQR 16.67-83.33 vs 6 weeks median 66.67, IQR 33.33-83.33; P=.04) and "Pain" (baseline median 33.33, IQR 16.67-50.00 vs 6 weeks median 16.67, IQR 0.00-33.33; P=.04). The "Global health/Overall QoL" scale remained stable (baseline median 58.33, IQR 45.83-77.08 vs 6 weeks median 62.50, IQR 41.67-75.00; P=.25). In the follow-up group (n=35), significant improvement was found in 3 domains: "Physical functioning" (baseline median 79.23, IQR 73.33-93.33 vs 6 weeks median 82.86, IQR 73.33-100.00; P=.03), "Cognitive functioning" (baseline median 62.38, IQR 50.00-83.33 vs 6 weeks median 69.52, IQR 50.00-100.00; P=.02), and "Social functioning" (baseline median 76.19, IQR 50.00-100.00 vs 6 weeks median 85.71, IQR 83.33-100.00; P=.05), as well as in the "Global health/Overall QoL" scale (baseline median 57.14, IQR 83.33-100.00 vs 6 weeks median 75.0, IQR 62.91-85.73; P<.001). CONCLUSIONS: In this study, we found an improvement in specific QoL scales for both participants in treatment and follow-up when using the app for 6 weeks. The global health or overall QoL score improved significantly in the follow-up group. In the treatment group, it remained stable. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/10098.

Cardiac Magnetic Resonance Identifies Responders to Cardiac Resynchronization Therapy with an Assessment of Septal Scar and Left Ventricular Dyssynchrony.

Background: The response to cardiac resynchronization therapy (CRT) depends on septal viability and correction of abnormal septal motion. This study investigates if cardiac magnetic resonance (CMR) as a single modality can identify CRT responders with combined imaging of pathological septal motion (septal flash) and septal scar. Methods: In a prospective, multicenter, observational study of 136 CRT recipients, septal scar was assessed using late gadolinium enhancement (LGE) (n = 127) and septal flash visually from cine CMR sequences. The primary endpoint was CRT response, defined as ≥15% reduction in LV end-systolic volume with echocardiography after 6 months. The secondary endpoint was heart transplantation or death of any cause assessed after 39 ± 13 months. Results: Septal scar and septal flash were independent predictors of CRT response in multivariable analysis (both p < 0.001), while QRS duration and morphology were not. The combined approach of septal scar and septal flash predicted CRT response with an area under the curve of 0.86 (95% confidence interval (CI): 0.78-0.94) and was a strong predictor of long-term survival without heart transplantation (hazard ratio 0.27, 95% CI: 0.10-0.79). The accuracy of the approach was similar in the subgroup with intermediate (130-150 ms) QRS duration. The combined approach was superior to septal scar and septal flash alone (p < 0.01). Conclusions: The combined assessment of septal scar and septal flash using CMR as a single-image modality identifies CRT responders with high accuracy and predicts long-term survival.

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial.

BACKGROUND: Intermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response. METHODS: In this trial, outpatients (N = 96, aged 22-65 years) meeting the diagnostic criteria for at least moderate depression (Montgomery and Aasberg Depression Rating Scale score ≥ 20) will be enrolled prospectively and receive ten, once-a-day sessions of either active iTBS or sham iTBS to the left DLPFC, localized via a neuronavigation system. Participants may have any degree of treatment resistance. Prior to stimulation, participants will undergo a thorough safety screening and a brief diagnostic assessment, genetic analysis of brain-derived neurotropic factor, 5-HTTLPR and 5-HT1A, and cerebral MRI assessments. A selection of neuropsychological tests and questionnaires will be administered prior to stimulation and after ten stimulations. An additional follow-up will be conducted 4 weeks after the last stimulation. The first participant was enrolled on June 4, 2022. Study completion will be in December 2027. The project is approved by the Regional Ethical Committee of Medicine and Health Sciences, Northern Norway, project number 228765. The trial will be conducted according to Good Clinical Practice and published safety guidelines on rTMS treatment. DISCUSSION: The aims of the present trial are to investigate the antidepressive effect of a 10-session iTBS protocol on moderately depressed outpatients and to explore the factors that can explain the reduction in depressive symptoms after iTBS but also a poorer response to the treatment. In separate, but related work packages, the trial will assess how clinical, cognitive, brain imaging and genetic measures at baseline relate to the variability in the antidepressive effects of iTBS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05516095. Retrospectively registered on August 25, 2022.

Hypothyroid women have persistently higher oxidative stress compared to healthy controls.

Objective: Some studies suggest that hypothyroidism is associated with increased oxidative stress. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents whole-body RNA and DNA oxidation, respectively. These biomarkers have only been explored sparsely in patients with thyroid disorders. Methods: In 45 Danish women with newly diagnosed hypothyroidism, we compared 8-oxoGuo and 8-oxodG before or shortly after initiating levothyroxine with the excretion rates at euthyroidism. We also compared the excretion of 8-oxoGuo and 8-oxodG in the patients after restored euthyroidism with 18 healthy control subjects. Results: Compared with baseline, none of the biomarkers changed significantly in the patients after becoming euthyroid. The geometric mean of 8-oxoGuo was 1.63 (95% CI: 1.49-1.78) nmol/mmol creatinine at baseline and 1.67 nmol/mmol at euthyroidism (95% CI: 1.53-1.83) (P = 0.39), while that of 8-oxodG was 1.28 nmol/mmol creatinine at baseline (95% CI: 1.14-1.44) and 1.32 nmol/mmol at euthyroidism (95% CI: 1.18-1.48), respectively (P = 0.47). The relative mean differences were 0.97 (95% CI: 0.91-1.04) for 8-oxoGuo and 0.97 (95% CI: 0.88-1.06) for 8-oxodG. At baseline, multiple linear regression revealed a positive association between free thyroxine and both biomarkers (8-oxoGuo, P < 0.001; 8-oxodG, P = 0.04). Furthermore, 8-oxoGuo was positively associated with age (P = 0.04) and negatively associated with thyrotropin (P = 0.02). In the control group, the geometric mean of 8-oxoGuo was 1.23 nmol/mmol creatinine (95% CI: 1.07-1.42), while that of 8-oxodG was 1.04 nmol/mmol creatinine (95% CI: 0.88-1.23). Thus, compared with control subjects, euthyroid patients showed a significantly higher level of both 8-oxoGuo (P < 0.001) and 8-oxodG (P = 0.03). Conclusion: In hypothyroid women, no significant effect of levothyroxine treatment on the oxidative stress biomarkers 8-oxoGuo and 8-oxodG could be demonstrated. However, the excretion of these biomarkers was significantly higher than in healthy controls.

Severity of hypothyroidism is inversely associated with impaired quality of life in patients referred to an endocrine clinic.

PURPOSE: We investigated the association between health-related quality of life (HRQL) and the severity of hypothyroidism at diagnosis in patients referred to a secondary hospital clinic. METHODS: Sixty-seven adult patients referred from primary care were enrolled. All patients had newly diagnosed hypothyroidism due to autoimmune thyroiditis and were treated with levothyroxine (LT4). The dose was adjusted according to thyroid function tests aiming at a normal plasma thyrotropin. Patients were stratified according to the severity of hypothyroidism in two different ways: the conventional approach (subclinical or overt hypothyroidism) and a novel approach according to the change (decrease or increase) in plasma level of free triiodothyronine index (FT3I) following LT4 treatment. The ThyPRO-39 questionnaire was used for measurement of HRQL at referral to the Endocrine Outpatient Clinic (higher score corresponds to worse HRQL). RESULTS: Free thyroxine index (FT4I) at diagnosis correlated positively with the scores on the Hypothyroid Symptoms and Tiredness scales (p = 0.018 for both). In accordance, patients with subclinical hypothyroidism (n = 36) scored higher on Hypothyroid Symptoms (p = 0.029) than patients with overt hypothyroidism (n = 31). The difference in HRQL was more pronounced if patients were stratified according to the dynamics in FT3I following LT4 treatment. Thus, patients who showed a decrease in FT3I following treatment (n = 24) scored significantly worse for Anxiety (p = 0.032) and Emotional Susceptibility (p = 0.035) than patients with an increase in FT3I (n = 43). CONCLUSION: Patients referred to an endocrine clinic with mild hypothyroidism had an impaired HRQL, compared to patients with more severe hypothyroidism. The most likely explanation of this finding is a lower threshold for seeking medical consultation and secondary care referral if HRQL is deteriorated. The dynamics in plasma FT3I following treatment may be more sensitive for such a discrimination in HRQL than a stratification according to the thyroid function tests at diagnosis.

Mechanical Dyssynchrony Combined with Septal Scarring Reliably Identifies Responders to Cardiac Resynchronization Therapy.

Background and aim: The presence of mechanical dyssynchrony on echocardiography is associated with reverse remodelling and decreased mortality after cardiac resynchronization therapy (CRT). Contrarily, myocardial scar reduces the effect of CRT. This study investigated how well a combined assessment of different markers of mechanical dyssynchrony and scarring identifies CRT responders. Methods: In a prospective multicentre study of 170 CRT recipients, septal flash (SF), apical rocking (ApRock), systolic stretch index (SSI), and lateral-to-septal (LW-S) work differences were assessed using echocardiography. Myocardial scarring was quantified using cardiac magnetic resonance imaging (CMR) or excluded based on a coronary angiogram and clinical history. The primary endpoint was a CRT response, defined as a ≥15% reduction in LV end-systolic volume 12 months after implantation. The secondary endpoint was time-to-death. Results: The combined assessment of mechanical dyssynchrony and septal scarring showed AUCs ranging between 0.81 (95%CI: 0.74-0.88) and 0.86 (95%CI: 0.79-0.91) for predicting a CRT response, without significant differences between the markers, but significantly higher than mechanical dyssynchrony alone. QRS morphology, QRS duration, and LV ejection fraction were not superior in their prediction. Predictive power was similar in the subgroups of patients with ischemic cardiomyopathy. The combined assessments significantly predicted all-cause mortality at 44 ± 13 months after CRT with a hazard ratio ranging from 0.28 (95%CI: 0.12-0.67) to 0.20 (95%CI: 0.08-0.49). Conclusions: The combined assessment of mechanical dyssynchrony and septal scarring identified CRT responders with high predictive power. Both visual and quantitative markers were highly feasible and demonstrated similar results. This work demonstrates the value of imaging LV mechanics and scarring in CRT candidates, which can already be achieved in a clinical routine.

Scar imaging in the dyssynchronous left ventricle: Accuracy of myocardial metabolism by positron emission tomography and function by echocardiographic strain.

PURPOSE: Response to cardiac resynchronization therapy (CRT) is reduced in patients with high left ventricular (LV) scar burden, in particular when scar is located in the LV lateral wall or septum. Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can identity scar, but is not feasible in all patients. This study investigates if myocardial metabolism by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contractile function by echocardiographic strain are alternatives to LGE-CMR. METHODS: In a prospective multicenter study, 132 CRT candidates (91% with left bundle branch block) were studied by speckle tracking strain echocardiography, and 53 of these by FDG-PET. Regional myocardial FDG metabolism and peak systolic strain were compared to LGE-CMR as reference method. RESULTS: Reduced FDG metabolism (<70% relative) precisely identified transmural scars (≥50% of myocardial volume) in the LV lateral wall, with area under the curve (AUC) 0.96 (95% confidence interval (CI) 0.90-1.00). Reduced contractile function by strain identified transmural scars in the LV lateral wall with only moderate accuracy (AUC = 0.77, CI 0.71-0.84). However, absolute peak systolic strain >10% could rule out transmural scar with high sensitivity (80%) and high negative predictive value (96%). Neither FDG-PET nor strain identified septal scars (for both, AUC < 0.80). CONCLUSIONS: In CRT candidates, FDG-PET is an excellent alternative to LGE-CMR to identify scar in the LV lateral wall. Furthermore, preserved strain in the LV lateral wall has good accuracy to rule out transmural scar. None of the modalities can identify septal scar. CLINICAL TRIAL REGISTRATION: The present study is part of the clinical study "Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy (CRID-CRT)", which was registered at clinicaltrials.gov (identifier NCT02525185).

Physical impairments among adults in Denmark: a register-based study.

BACKGROUND: Knowledge of the prevalence and socio-demographic characteristics of physical impairments is limited. This study aimed to determine the prevalence of physical impairments among adults in Denmark, both in total and according to nine common diagnostic subgroups, describe the socio-demographic and socio-economic profile, and compare the data with those of the general adult population. METHODS: This descriptive, cross-sectional, register-based study evaluated the general socio-demographic and socio-economic variables, including sex, age, geographical region, origin, educational level, occupation, marital status, and disability level, of adults with physical impairments extracted by diagnosis from the Danish National Patient Register and Statistics Denmark by 31 December 2018. These data were compared with those of the general adult population in Denmark extracted from Statistics Denmark by January 2019. RESULTS: In total, 606,857 adults with physical impairments were identified. Of the nine selected diagnoses, osteoarthritis (69.4%) was the most prevalent, followed by acquired brain injury (29.0%), rheumatoid arthritis (6.7%), multiple sclerosis (2.6%), spinal cord injury (1.5%), cerebral palsy (1.2%), amputation (0.7%), muscular dystrophy (0.5%), and poliomyelitis (< 0.1%). There were large variations in the socio-demographic and socio-economic profile between the nine diagnostic subgroups. The adults with physical impairments were more often women, were older, were less often immigrants and employed adults, had a lower educational level, and were more commonly married than the general adult population. Only the geographical region did not differ. CONCLUSION: The nine subgroups with diagnoses related to the musculoskeletal system represent 13% of the adult Danish population. The socio-demographic and socio-economic profile varied largely between the nine diagnostic subgroups, and almost all variables differed significantly between adults with physical impairments and the general adult population in Denmark. These findings reveal patterns and trends on socio-demographic and socio-economic variables essential for future planning at a societal level, including the healthcare and social sectors.

The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21.

Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2H-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N-acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiol-based nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made clear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.

Functional rewiring of G protein-coupled receptor signaling in human labor.

Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor.

Communication about physical activity to reduce vascular erectile dysfunction - A qualitative interview study among men in cardiac rehabilitation.

BACKGROUND: Physical activity, a core intervention in cardiac rehabilitation, can reduce vascular erectile dysfunction (ED). ED is a common sensitive problem for men with cardiac diseases, decreasing their quality of life. Cardiac health professionals rarely provide information about ED or its relation to physical activity. Developing health professionals' communicative component of the complex intervention 'Physical Activity to reduce Vascular Erectile Dysfunction' (PAVED) is important. Understanding the receiver needs is essential in designing a complex intervention. AIM: To elucidate men's perspectives on cardiac health professionals' communication about PAVED. ETHICAL ISSUES: An Institutional Data Protection Agency approved the study. METHODS: An interpretive data-driven thematic analysis was applied to individual, qualitative semi-structured interviews with 20 Danish men attending cardiac rehabilitation. RESULTS: The men wanted health professionals' communicating about ED, as it was perceived as a major problem diminishing masculinity and tabooed by health professionals. Men wanted help for self-help, which may be possible with the aid of competent health professionals' communication about how to prevent, reduce and cope with ED - including information about PAVED. The men wanted health professionals' communication about ED in various contexts: general information in groups, sexual counselling for individuals and couples and written material. STUDY LIMITATIONS: Recruitment was done from a Danish municipality's cardiac rehabilitation, and the transferability of the results may be limited to similar contexts. CONCLUSION: Erectile dysfunction was experienced as a major biopsychosocial problem for the men and their partners. The men had a need for health professionals' communication about sexuality, ED and information about PAVED as well as about prevention, reduction and management of ED. The men had a need for professional communication about sexual health.